Typhoid fever (TF) remains a serious and frequent cause of morbidity and mortality in underdeveloped nations; there is yet, no satisfactory vaccine for its prevention. The immunopathogenic role of the capsular polysaccharide of Salmonella typhi (Vi antigen), the causative agent, remains controversial. There is indirect evidence that Vi antibodies could confer protection against typhoid fever. TF is a disease of humans only; clinical studies are required to evaluate the effectiveness of the Vi vaccines. In collaboration with Dr. H. Kornhof, South African Institute of Medical Research, Dr. I.L. Acharya, Infectious Disease Hospital, Kathmandu, Nepal, and Dr. Ramesh Kumar, All India Institute of Medical Sciences, New Delhi, India, we are studying typhoid fever and Vi antibodies. An accurate, sensitive radioimmunoassay for Vi antibodies has been established; it is a reliable method to identify carriers. Studies in U.S. armed forces recruits showed the Vi elicited higher levels of Vi antibodies than cellular typhoid vaccine. Three surveys in individuals of various ages in Chile, Eastern Transvaal, and Nepal, showed that adults had considerably higher Vi antibodies than those in the U.S. Placental transmission of Vi antibodies was poor. There is an age-related development of Vi antibodies; the highest levels here were in young adults. Vi polysaccharide with low LPS content and high molecular weight prepared by the Institut Merieux, was studied for its safety and immunogenicity in Eastern Transvaal and in Nepal. The Vi elicited no serious side reactions and both 25 and 50 micrograms stimulated a 4-fold or greater response in at least 90 percent of vaccinates. Effectiveness trials are now underway. A Vi-cholera toxin conjugate has been prepared and standardized; it is about 15 times more immunogenic in mice than the Vi alone. Clinical studies with this new vaccine are being planned.